Inhibitors of cyclic amp phosphodiesterases

Abstract

Recombinant fission yeast cells and methods of using them are described, which provide for identification of chemical and biological inhibitors or activators of a target exogenous phosphodiesterase (PDE). The invention provides, in some aspects, compounds that inhibit cAMP PDE activity and compositions that include such compounds. The invention, in part, also includes methods of using cAMP PDE-inhibiting compounds in the treatment of cAMP PDE-associated diseases and / or disorders.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of U.S. provisional application 60 / 925,503, filed Apr. 20, 2007. The entire teachings of the referenced provisional application are incorporated by reference herein in its entirety.GOVERNMENT SUPPORT[0002]The invention was made with government support under grant GM46226 and grant GM79662, each awarded by the National Institutes of Health. The United States Government has certain rights in the invention.FIELD OF THE INVENTION[0003]The present invention provides methods for treating inflammatory diseases comprising either the administration of a dual phosphodiesterase 7-phosphodiesterase 4 (PDE7-PDE4) inhibitors, or the simultaneous or sequential co-administration of a selective PDE7 inhibitors together with a selective PDE4 inhibitors. The present invention further relates to pharmaceutical compositions containing these inhibitors, and the use of these inhibitors in the treatment of inflammatory diseases.BACKGROUND OF THE...

AI Technical Summary

Benefits of technology

[0018]Co-administration of PDE inhibitors, which may be selective for the PDE family, a specific PDE subfamily, or a specific isoform of a PDE-subfamily member, such as a selective PDE4 inhibitor with a selective PDE7 inhibitor, or administration of a dual PDE7-PDE4 inhibitor, can be used to increase therapeutic effectiveness, and / or reduce toxicity and / or side effects (such as nausea) over presently-available approaches. The combined activity of PDE4 and PDE7 or dual PDE7 / 4 inhibitors may be especially useful in treating a wide variety of immune and inflammatory disorders as an immunosuppressant therapy. PDE7 inhibitors act by inhibiting a very early stage of the T cell activation cascade. PDE4 inhibition decreases the production of the pro-inflammatory cytokines such as Tumor Necrosis Factor alpha, (TNF-α) in monocytes and macrophages, as well as affect granulocytes, such as neutrophils. Dual PDE4 / 7 inhibitors or co-administration of selective PDE4 and PDE7 inhibitors are expected to be particularly useful in treating disorders that involve one or more inflammatory response alleviated, at lease in part, by PDE4 inhibition (e.g., via decreased mast cell, basophil and neutrophil degranulation and monocyte and macrophage production of pro-inflammatory cytokines such as TNF-α), and / or are alleviated at least in part by PDE7 inhibition (e.g., though decreased T cell activation), e.g., disorders such as rheumatoid arthritis, inflammatory bowel disease (IBD), psoriasis, asthma, chronic obstructive pulmonary disease (COPD), lupus, visceral pain, osteoarthritis, osteoporosis, allergic rhinitis, cancer, acquired immune deficiency syndrome, allergy, fertility diseases, and multiple sclerosis among others. A PDE4-PDE7 inhibitor combination is also expected to have a decreased potential for clinically significant side effects compared to current immunosuppressants.

Problems solved by technology

The presence of multiple PDE isoenzymes in various tissues complicates efforts to determine the relative roles of specific enzymes in any given biological process.

PDE8A was not able to be inhibited with dipyridamole, which has been shown to inhibit PDE8A12, and this result may have been due to a permeability problem in the yeast.

Moreover, because this platform identifies compounds based on stimulation of cell growth, it will not detect compounds that, while inhibiting PDEs in vitro, are too cytotoxic or cell-impermeable for therapeutic use.

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